Despite intensive study, the immune responses associated with protective immunity against HIV infection remain poorly understood. Immunization with attenuated SIV strains has proven to be one of the most effective means to induce protection in nonhuman primates, and analysis of protective immunity in this model thus offers an ideal research setting in which to define specific mechanisms that may play a role in mediating protection. Work conducted in the previous funding period has provided a detailed description of the array of immune responses induced by attenuated SIV and provided correlative evidence for roles for both cellular and humoral immune responses in protecting against infection with pathogenic SIV strains. However, increasing evidence suggests that identification of the mechanisms of protection in this model is likely to be complex, is likely to represent the contributions of multiple arms of the immune system and may vary depending on the challenge model and host genotype. The overall goal of the current proposal is to further dissect the relative roles of cellular and humoral immune responses in mediating protection induced by live attenuated SIV strains. Specific aims include: 1. To examine the role of CD8+ T cell responses in mediating protection against vaginal challenge in SIVmac239delta3-vaccinated macaques. 2. To examine the relative contributions of cellular and humoral immune responses in mediating protection against intravenous challenge in (3-vaccinated macaques. 3. To carry out a detailed examination of early virologic and immunologic events occurring following intravenous challenge of macaques immunized with attenuated SIV. 4. To examine the evolution of CD8+ T cell responses in delta3-vaccinated macaques.